Treatment of cancer metastasis, the spread and growth of tumour cells to distant sites, presents a significant challenge despite the identification of a number of mediators that are implicated in the process. Indeed, spread of cancer to distant sites is almost universally associated with poor prognosis and, in many cases, resistance to effective treatment. For example, in childhood acute lymphoblastic leukaemia (ALL) certain high-risk cytogenetic subtypes not only have higher relapse rate but are also more likely to relapse in extramedullary sites such as the CNS. Methods for identification of tumour subtypes that are prone to spread and/or relapse are currently sub-optimal. In the case of ALL, current methods for establishing a prognosis involve, for example, cytogenetic analysis (e.g. FISH) requiring specialist knowledge and expertise, particularly for interpretation of results.
Epithelial-mesenchymal transition (EMT) occurs during embryonic development and is believed to be important for the metastatic spread of epithelial tumours [17]. It is characterized by an E- to N-cadherin switch, increased vimentin expression, upregulation of E-cadherin repressor molecules and increased gelatinase activity and motility [18].
CD26 is a cell surface protease which cleaves the chemokine CXCL12 [19]. CXCL12 has been shown to regulate many biological processes but also plays an important role in tumourigenesis [20, 21]. CXCL12 binds to the widely expressed cell surface chemokine receptor CXCR4 [22, 23] and to the recently identified receptor CXCR7/RDC1 [24] leading to a signalling cascade resulting in downstream phosphorylation of proteins such as ERK1/2 and AKT [25, 26]. Like CXCL12, CXCR4 expression has also been associated with tumourigenesis in many cancers including breast, ovarian, renal, prostate, and neuroblastoma [20-22]. These CXCR4-expressing tumours preferentially spread to tissues that highly express CXCL12, including brain, lung, liver, lymph nodes and bone marrow [20-22].
The chemokine receptor CXCR6, which binds the ligand CXCL16 is upregulated in certain tumours, for example human prostate cancer, and increases the metastatic progression of these cells by enhancing CXCL16 mediated chemotaxis [51].
5T4 oncofetal glycoprotein was discovered while searching for molecules with invasive properties likely to be shared by trophoblast and cancer cells [1]. It is expressed by many different carcinomas while showing only low levels in some normal tissues [2]. 5T4 expression has been shown to influence adhesion, cytoskeletal organization and motility, properties [3-5] which might account for its association with poorer clinical outcome in some cancers [6-9]. The ≈72 kDa transmembrane molecule has an N-glycosylated extracellular domain with two leucine rich repeat (LRR) regions with associated N and C terminal flanking regions separated by a hydrophilic sequence as well as a short cytoplasmic region [10, 11]. Leucine rich repeats are found in proteins with diverse functions and are frequently associated with protein-protein interaction [12]. It has recently been shown that upregulation of 5T4 expression is a marker of loss of pluripotency in the early differentiation of human and murine embryonic stem cells [13, 14] and forms an integrated component of an EMT [15-16].
Despite advances in the treatment of many cancers, provision of therapeutic agents and treatment strategies for preventing or limiting the spread of cancer cells is currently hampered by an incomplete picture of the mechanistic details of metastasis. Accordingly, there remains a need for methods to identify and utilise agents that inhibit the spread of cancer cells, and methods to identify tumours at high risk of metastasis.